A striking contrast exists between public enthusiasm for vitamin E supplements for the prevention and treatment of chronic disease and the evidence from multiple randomized controlled trials, which shows no health benefit from their use. Recent trials of high-dose vitamin E (400 IU or more per day) have suggested evidence of harm, noting increases in all-cause mortality, which were not statistically significant, compared with patients taking placebo. Miller and colleagues performed a meta-analysis to examine the dose-response relationship between vitamin E supplementation and all-cause mortality.

Nineteen randomized controlled trials from 1993 to 2004 met prespecified inclusion criteria, which were all-cause mortality data, a minimum of 10 deaths, and follow-up periods of at least one year. Trial sizes ranged from 196 to 29,584 participants. Trials were classified as low or high dose based on an arbitrary cutoff of 400 IU per day. Eight trials were low dose; 11 were high dose. The experimental groups in 10 of the trials took other dietary supplements such as vitamin C, beta-carotene, selenium, and zinc. Study populations varied from healthy middle-aged adults to institutionalized older adults with coronary artery disease and other chronic diseases. High-dose trials were more likely to include the latter group of patients.

As a whole, all-cause mortality in patients taking vitamin E did not differ from that in the control groups (pooled risk ratio = 1.01, P > .2). However, the dose-response analysis observed a progressive increase in all-cause mortality beginning at 150 IU per day and becoming statistically significant at doses of 1,100 IU or more per day. When results were stratified into low- and high-dose groups, the pooled risk difference for high-dose vitamin E was 39 excess deaths per 10,000 persons (risk ratio = 1.04, P = .035) compared with placebo.

To control for the variability across trials, the authors separately analyzed the contribution of each trial to the overall result. Each trial’s effect on the overall risk was roughly proportional to its size. The increased mortality associated with high-dose vitamin E persisted even when individual high-dose studies were excluded. Controlling for the use of other supplements increased the risk of high-dose vitamin E to 63 excess deaths per 10,000 persons.

In concordance with previous studies, the authors conclude that vitamin E supplementation does not reduce mortality. In addition, they contend that their finding of a consistent relationship between increasing amounts of vitamin E and all-cause mortality support the avoidance of supplements at dosages of 400 IU per day or greater. They caution that this recommendation may not apply to healthy adults, who were included in only two of the 11 high-dose trials.

editor’s note: In an accompanying editorial, Greenberg1 reflects on how uncontrolled epidemiologic observations and laboratory experiments fueled the widespread belief that high doses of antioxidants such as vitamin E are good for one’s health. He cautions, however, that the heterogeneity of populations included in this meta-analysis, as well as the concomitant use of other supplements in a majority of the trials, call into question the authors’ conclusion that high-dose vitamin E increases all-cause mortality. However, he agrees with the authors that physicians should not prescribe vitamin E supplements to prevent or treat disease.—k.w.l.